Objective:Urinary tract infection(UTI)is a common cause of morbidity and hospitalisation in the population worldwide.Upper UTI is indolent and causes subclinical acute kidney injury(AKI)resulting in preventable cause ...Objective:Urinary tract infection(UTI)is a common cause of morbidity and hospitalisation in the population worldwide.Upper UTI is indolent and causes subclinical acute kidney injury(AKI)resulting in preventable cause of scarring of renal parenchyma.We explored urinary and serum levels of kidney injury molecule-1(KIM-1),haematological parameters and quantitative urine microscopy parameters to predict kidney injury.Methods:Neutrophilelymphocyte ratio(NLR)is obtained by dividing absolute neutrophil count with absolute lymphocyte count.Quantitative urine sediment microscopy was performed and correlated with clinical,biochemical and haematological findings to predict AKI in patients with UTI.Quantitative ELISA was performed for serum and urine levels of KIM-1.Seventy two adult patients with UTI were enrolled,45 of whom had AKI while 27 were in the non-AKI group.Results:NLR(p=0.005)and renal tubular epithelial cell-granular cast score in quantitative urine microscopy(p=0.008)are strong predictors of AKI in patients with UTI while rest of quantitative urine microscopy parameters and serum and urinary levels of KIM-1 molecule were not found to be useful in prediction of AKI.Conclusion:NLR in haemogram is a novel and useful biomarker for predicting AKI in patients with UTI.展开更多
Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mecha...Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.展开更多
Chronic obstructive pulmonary disease(COPD),a disease responsible for early mortality worldwide,is well accepted to be associated with periodontitis epidemiologically.Although both of the diseases are the multi-microb...Chronic obstructive pulmonary disease(COPD),a disease responsible for early mortality worldwide,is well accepted to be associated with periodontitis epidemiologically.Although both of the diseases are the multi-microbial inflammatory disease,the precise underlying mechanisms by which periodontitis influences the progression of COPD remains largely unknown.Here,we established COPD accompanied with periodontitis mouse models and observed the pronounced progress in pulmonary symptoms and histopathology,cha racterized by poorer respiratory function,thicke ned bronchial walls,and increased neutrophils infiltration in lung tissue.Mechanistically,periodontitis pathogen Porphyromonas gingivalis(P.gingivalis)relocated in the lung through the respiratory tract and LPS from P.gingivalis promoted the secretion of chemokines CXCL2 and G-CSF of alveolar epithelial cells through NF-κB and p38 MAPK pathways to recruit neutrophils.Furthermore,exposure to P.gingivalis of infiltrated neutrophils released matrix metallopeptidase-8(MMP-8)and neutrophil elastase(NE),which aggravated airway inflammation and tissue damage.These findings indicated that periodontitis could exacerbate COPD via its pathogen P.gingivalis,which translocated in the lung and stimulated neutrophil chemotaxis and activation in the lung.展开更多
Objectives Neutrophil extracellular traps(NETs)have emerged as critical effectors in immune defense but also as potential drivers of tissue damage in chronic inflammatory diseases.Their role in periodontitis,a highly ...Objectives Neutrophil extracellular traps(NETs)have emerged as critical effectors in immune defense but also as potential drivers of tissue damage in chronic inflammatory diseases.Their role in periodontitis,a highly prevalent condition characterized by dysregulated host–microbe interactions,remains incompletely defined.This systematic review aimed to synthesize,for the first time,ex vivo human evidence on the presence,activity,and clinical significance of NETs in periodontitis.Methods A comprehensive search of Medline,Web of Science,and Scopus was conducted up to August 2025.Eligible studies included ex vivo human investigations assessing NETs or NET markers in gingival tissues,gingival crevicular fluid,saliva,blood,or biofilms from patients with periodontitis.Study selection,data extraction,and risk-of-bias assessment were conducted in duplicate,and the protocol was registered in PROSPERO(CRD420251109174).Results Seventeen studies met the inclusion criteria.NET markers such as citrullinated histone H3(CitH3),myeloperoxidase(MPO),and neutrophil elastase were consistently elevated in periodontitis samples compared with controls.Several studies reported a reduction in NET levels or improved NET degradation following periodontal therapy.NETs were also implicated in biofilm stability and in systemic associations with rheumatoid arthritis and chronic kidney disease.However,heterogeneity in methodologies,small sample sizes,and inconsistent marker use limited comparability across studies.Conclusions Ex vivo evidence indicates that aberrant NET formation and impaired clearance contribute to periodontal inflammation and tissue destruction.Nonetheless,methodological variability and risk of bias constrain definitive conclusions.Standardization of detection methods,consensus on marker panels,and exploration of neutrophil subsets and systemic confounders are essential to establish NETs as reliable biomarkers and therapeutic targets in periodontitis.展开更多
Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modu...Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization.’ There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations(microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.展开更多
BACKGROUND The objective of the current study was to elucidate the clinical mechanism through which phospholipase D2(PLD2)exerted a regulatory effect on neutrophil migra-tion,thereby alleviating the progression of acu...BACKGROUND The objective of the current study was to elucidate the clinical mechanism through which phospholipase D2(PLD2)exerted a regulatory effect on neutrophil migra-tion,thereby alleviating the progression of acute pancreatitis.AIM To elucidate the clinical mechanism through which PLD2 exerted a regulatory effect on neutrophil migration,thereby alleviating the progression of acute pan-creatitis.METHODS The study involved 90 patients diagnosed with acute pancreatitis,admitted to our hospital between March 2020 and November 2022.A retrospective analysis was conducted,categorizing patients based on Ranson score severity into mild(n=25),moderate(n=30),and severe(n=35)groups.Relevant data was collected for each group.Western blot analysis assessed PLD2 protein expression in patient serum.Real-time reverse transcription polymerase chain reaction was used to evaluate the mRNA expression of chemokine receptors associated with neutrophil migration.Serum levels of inflammatory factors in patients were detected using enzyme-linked immunosorbent assay.Transwell migration tests were conducted to compare migration of neutrophils across groups and analyze the influence of PLD2 on neutrophil migration.RESULTS Overall data analysis did not find significant differences between patient groups(P>0.05).The expression of PLD2 protein in the severe group was lower than that in the moderate and mild groups(P<0.05).The expression level of PLD2 in the moderate group was also lower than that in the mild group(P<0.05).The severity of acute pancreatitis is negatively correlated with PLD2 expression(r=-0.75,P=0.002).The mRNA levels of C-X-C chemokine receptor type 1,C-X-C chemokine receptor type 2,C-C chemokine receptor type 2,and C-C chemokine receptor type 5 in the severe group are significantly higher than those in the moderate and mild groups(P<0.05),and the expression levels in the moderate group are also higher than those in the mild group(P<0.05).The levels of C-reactive protein,tumor necrosis factor-α,interleukin-1β,and interleukin-6 in the severe group were higher than those in the moderate and mild groups(P<0.05),and the levels in the moderate group were also higher than those in the mild group(P<0.05).The number of migrating neutrophils in the severe group was higher than that in the moderate and mild groups(P<0.05),and the moderate group was also higher than the mild group(P<0.05).In addition,the number of migrating neutrophils in the mild group combined with PLD2 inhibitor was higher than that in the mild group(P<0.05),and the number of migrating neutrophils in the moderate group combined with PLD2 inhibitor was higher than that in the moderate group(P<0.05).The number of migrating neutrophils in the severe group+PLD2 inhibitor group was significantly higher than that in the severe group(P<0.05),indicating that PLD2 inhibitors significantly stimulated neutrophil migration.CONCLUSION PLD2 exerted a crucial regulatory role in the pathological progression of acute pancreatitis.Its protein expression varied among patients based on the severity of the disease,and a negative correlation existed between PLD2 expression and disease severity.Additionally,PLD2 appeared to impede acute pancreatitis progression by limiting neutrophil migration.展开更多
Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed t...Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes(M2-Exos).We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition.Additionally,we identified that M2-Exos’therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adenoassociated virus respectively.Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells.These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.展开更多
Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019(COVID19).In older individuals,a dysregulated immune response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2...Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019(COVID19).In older individuals,a dysregulated immune response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection contributes to disease severity;however,the underlying mechanism remains elusive.In this study,we established an aging mouse model of COVID-19,successfully replicating the development of a relatively severe disease in older adults.Further single-cell transcriptome analysis revealed a distinct immune cell landscape in the infected lungs,accompanied by an over-activated inflammatory response,especially in aging mice.Compared to young mice,aging mice showed extensive neutrophil activation,NETosis,and a dramatic decrease in the number of alveolar macrophages(AMs).Moreover,as important executors of efferocytosis,AMs exhibited a low efferocytotic gene signature and downregulation of multiple efferocytosis receptors in aged mice.Further analysis indicated that the efferocytosis of neutrophils,whether undergoing apoptosis or NETosis,was compromised after SARS-CoV-2 infection.Since efferocytosis is a key process in inflammatory resolution,impaired efferocytosis may contribute to hyperinflammation in aging lungs.Our study reveals the characteristics and role of efferocytosis in aging mice after SARS-CoV-2 infection and provides valuable insights for the potential treatment of COVID-19.展开更多
Inflammatory bowel disease(IBD)comprises a heterogeneous group of chronic inflammatory conditions of the intestine.Current therapeutic strategies primarily focus on maintaining remission and mitigating the secondary e...Inflammatory bowel disease(IBD)comprises a heterogeneous group of chronic inflammatory conditions of the intestine.Current therapeutic strategies primarily focus on maintaining remission and mitigating the secondary effects rather than reversing its pathogenic mechanisms(Jeong et al.,2019).The pathogenesis of IBD involves intestinal barrier dysfunction,tissue damage,and dysregulated innate and adaptive immune responses(de Souza et al.,2017).Elevated neutrophil activity has been reported in IBD(Danne et al.,2024),yet the precise roles and mechanisms of neutrophils in disease progression remain to be elucidated.展开更多
Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell...Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell transcriptomics(scRNA-seq)and spatial transcriptomics(ST)to highlight the pivotal role of tumor-associated neutrophils(TANs)among tumor-infiltrating immune cells and their therapeutic response to MTC.MNDA+TANs with anti-tumor activity(N1-phenotype)are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion,and these TANs are characterized by enhanced cytotoxicity,ameliorated hypoxia,and upregulated IL1B,activating T&NK cells and fibroblasts via IL1B-IL1R.In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC,fibroblasts accumulated in the tumor front(TF)can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs(pro-tumor phenotype)via CXCL12-CXCR4,which results in the aggregation of N1-TANs and extracellular matrix(ECM)deposition.In addition,we construct an N1-TANs marker,MX2,which positively correlates with better prognosis in LSCC patients,and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin(H&E)-stained images so as to conveniently guide decision making in clinical practice.Collectively,our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.展开更多
Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(...Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(anti⁃MDA5+)dermatomyositis(DM)develop into the rapidly progressive interstitial lung disease(RPILD).Methods:We retrospectively analyzed the clinical and laboratory data of 124 anti⁃MDA5+DM patients from the First Affiliated Hospital of Nanjing Medical University between March 2019 and September 2023.We identified independent risk factors associated with the development and mortality of RPILD with the Cox regression analysis,and determined the optimal cut⁃off values for predicting adverse outcomes with the receiver operating characteristic(ROC)curve analysis.Results:Among the 124 patients,36 patients(29.03%)developed RPILD,and 39 patients(31.45%)died during the follow⁃up period.The results of multivariate Cox regression analysis showed that the elevated NLR was an independent risk factor for RPILD development,while the elevated SII expression was independently associated with the increased mortality of RPILD.Based on the ROC curve analysis,NLR>6.12 was a predictor for RPILD,and SII>875.79 was associated with increased mortality risk of RPILD.Conclusion:Both NLR and SII are accessible,cost⁃effective,and reliable prognostic indicators for the prognosis of patients with anti⁃MDA5^(+)DM,providing a valuable guidance for clinical management and risk stratification of the disease.展开更多
In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to elimin...In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species.Besides,neutrophils will accumulate at the inflammatory site and release NETs,which are composed of histones,DNA and granular proteins.Traumatic heterotopic ossification(THO)was generally believed to develop through four stages:Inflammation,chondrogenesis,osteogenesis,and bone maturation.Thus,it can be seen that THO was related to inflammation and bone formation.Apart from immune and infectious diseases,recent studies have also shown that NETs play a significant role in the pathogenesis of THO.This article focuses on elaborating the role of NETs in the onset of THO,discussing the existing problems in the current research and outlining future directions.展开更多
BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)is a prevalent chronic liver disorder driven by obesity and metabolic dysfunction.MASLD progresses to metabolic dysfunction-associated steatohe...BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)is a prevalent chronic liver disorder driven by obesity and metabolic dysfunction.MASLD progresses to metabolic dysfunction-associated steatohepatitis,which is characterized by inflammation,hepatocyte injury,and fibrosis,increasing the risk of cirrhosis and liver failure.Recent studies suggest that neutrophil extracellular traps(NETs)and extracellular DNA(ecDNA)contribute to liver inflammation and fibrogenesis.However,their role in MASLD pathogenesis remains incompletely understood.AIM To investigate the dynamics of circulating NETs and ecDNA as potential biomarkers of liver injury in MASLD.METHODS Using three complementary mouse models,thioacetamide(TAA)-induced fibrosis,choline-deficient L-amino acid-defined(CDAA)diet-induced metabolic dysfunction-associated steatohepatitis,and cafeteria(CAF)diet-induced MASLD,we assessed the association between NET-related markers and liver damage.Blood samples were collected biweekly to analyze ecDNA and NET markers,including myeloperoxidase(MPO)and MPO-DNA complexes,using ELISA and real-time PCR.Liver histopathology was assessed for inflammation,fibrosis,and neutrophil infiltration.RESULTS The TAA and CDAA models exhibited significant liver injury,characterized by increased plasma alanine aminotransferase and aspartate aminotransferase levels,hepatocellular damage,and fibrosis.Elevated circulating NET markers(MPO and ecDNA)were observed in these models,with a strong correlation between NET formation and liver pathology.The CAF diet model induced steatosis but failed to elicit significant liver fibrosis or an increase in NET markers,suggesting that NETosis is associated with more severe liver damage.Notably,ecDNA and MPO levels correlated with neutrophil infiltration and fibrosis scores,indicating their potential as biomarkers of MASLD progression.CONCLUSION NETosis and ecDNA levels reflect liver injury severity in MASLD.NET markers and liver fibrosis were strongly associated in TAA and CDAA models,whereas CAF model showed minimal NET involvement.展开更多
Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as...Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.展开更多
Tumor-associated neutrophils(TANs)exhibit highly func-tional heterogeneity across cancers.Although TANs pro-mote inflammatory responses and contribute to tumor clearance,they frequently undergo context-dependent repro...Tumor-associated neutrophils(TANs)exhibit highly func-tional heterogeneity across cancers.Although TANs pro-mote inflammatory responses and contribute to tumor clearance,they frequently undergo context-dependent reprogramming within the tumor microenvironment(TME)into highly immunosuppressive phenotypes that facilitate cancer dissemination and immunotherapy resist-ance1,2.We contend that an underappreciated,upstream determinant of this divergence is the maturation stage of TANs3,4.The developmental stage of TANs determines the migration patterns and constrains the functional capacity,and the developmental stage also constrains the extent of TME-driven re-education,together shaping pro-or anti-tu-mor outcomes3-5.In this Perspective,we place maturation at the core of TAN biology and discuss current definitions for TAN developmental stages and the measurable mark-ers that researchers and clinicians can use(Figure 1).In addition,spatial and temporal transitions in TAN matu-ration stages and the factors that govern these transitions are elucidated.We explain how maturation status shapes TAN function and articulate the key differences between mouse and human TAN maturation systems to highlight the value of human immune system(HIS)mouse models.Based on this framework,functional biomarkers and signa-tures of TAN maturation are introduced and we show how to embed them into patient stratification and longitudinal monitoring.Finally,we outline immunotherapy strategies targeting TAN maturation,selecting interventions guided by maturation markers to reinforce treatment benefits for cancer patients.展开更多
Neutrophils are the protagonists of the host immune response,possessing potent antimicrobial and inflammatory capacities.The neutrophil reservoir as well as the development,mobilization,chemotaxis,pro-inflammatory act...Neutrophils are the protagonists of the host immune response,possessing potent antimicrobial and inflammatory capacities.The neutrophil reservoir as well as the development,mobilization,chemotaxis,pro-inflammatory activity,and clearance of neutrophils are strictly regulated to prevent inflammation-induced tissue damage.Inflammation pervades almost every type of cancer.However,there is growing awareness that although the tumor microenvironment has the capacity to recruit neutrophils,the functions are diverse and include roles other than that of sentinels in cancer.This review highlights the heterogeneity of neutrophils in tumors,discusses the dual role of neutrophils as angels and demons in tumorigenesis,invasion,and metastasis,and examines the potential of neutrophils as targets in clinical therapy.展开更多
Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins...Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins released by neutrophils,contribute significantly to both inflammation and thrombosis.This manuscript offers a comprehensive review of the recent literature on the involvement of NET in atherosclerosis,highlighting their interactions with various pathophysiological processes and their potential as biomarkers for CVD.Notably,the impact of radiation on NET formation is explored,emphasising how oxidative stress and inflammatory responses drive NET release,contributing to plaque instability.The role of histones,particularly citrullinated histones,in endothelial dysfunction and plaque progression is discussed,highlighting their significance in the pathophysiology of atherosclerosis.Furthermore,the complex relationship between lipoproteins and NET formation is examined,with a focus on how elevated low-density lipoprotein(LDL)and decreased high-density lipoprotein(HDL)levels facilitate NET release,thus promoting vascular inflammation and plaque instability.The influence of cholesterol on NET formation is also explored,underscoring its contribution to plaque development and stability.The role of Peptidylarginine deiminase 4(PAD4)in the regulation of NETosis is reviewed,with attention given to how PAD4-driven citrullination of histones affects atherosclerosis progression.Moreover,the manuscript examines the potential of NET components—such as double-stranded DNA,myeloperoxidase–DNA complexes,and citrullinated histone H3—as biomarkers for assessing disease severity and predicting adverse cardiovascular events,including ST-elevation myocardial infarction(STEMI)and stroke.Elevated levels of these biomarkers correlate with worse clinical outcomes,suggesting their utility in guiding therapeutic interventions.In contrast to the existing body of work,this review highlights the novelty of integrating recent findings on NET interactions with lipid metabolism,histone modifications,and PAD4 activity in the context of atherosclerosis.Overall,NET plays an integral role in the inflammatory and thrombotic processes underpinning atherosclerosis,and their components hold promise as both diagnostic markers and therapeutic targets in cardiovascular disease management.展开更多
Neutrophil extracellular traps(NETs)have been the subject of research in the field of innate immunity since they were first described two decades ago.NETs are fibrous network structures released by neutrophils under s...Neutrophil extracellular traps(NETs)have been the subject of research in the field of innate immunity since they were first described two decades ago.NETs are fibrous network structures released by neutrophils under specific stimuli,including DNA,histones,and a variety of granular proteins.NETs have been widely studied in the fields of infectious and immune diseases,and new break-throughs have been made in the understanding of disease pathogenesis and treatment.In recent years,studies have found that NETs play an important role in the occurrence and development of osteoarticular diseases.This article reviews the progress in the research of NETs in common osteoarticular diseases such as rheumatoid arthritis,ankylosing spondylitis,gouty arthritis,osteonecrosis of the femoral head,osteoarthritis,and joint fibrosis,including the formation mecha-nism of NETs and its role in inflammation,joint destruction,pain and other pa-thological processes.The problems existing in current research are discussed,along with future research directions,to provide a reference for the in-depth study of osteoarticular diseases and the development of new treatment strategies.展开更多
ABSTRACT:Background:After ischemic stroke,neutrophils hyperactivate,increasing in number and worsening inflammation,causing neural damage.Prior scRNA-seq showed Lrg1 modulates cells subsentence to cerebral ischemiarep...ABSTRACT:Background:After ischemic stroke,neutrophils hyperactivate,increasing in number and worsening inflammation,causing neural damage.Prior scRNA-seq showed Lrg1 modulates cells subsentence to cerebral ischemiareperfusion injury,but its mechanism in regulating neutrophil accumulation/differentiation post-injury is unclear.Methods:Lrg1 knockout impact on neutrophil accumulation was assessed via immunofluorescence and western blot.Three-dimensional reconstruction of immunofluorescent staining analyzed cell-cell interactions among neutrophils and microglia.scRNA-seq of WT and Lrg1^(-/-)mice from GSE245386 and GSE279462 was conducted.Each group conducted oxidative phosphorylation scoring via Gene Set Enrichment Analysis(GSEA),while Metascape was employed to perform GO and KEGG enrichment analyses for elucidating functional mechanisms.CellChat exhibited cell-cell communication.Furthermore,alterations in microglial phagocytic activity were evaluated by immunostaining for CD68,a well-established marker of phagolysosomal activity in phagocytic cells.Brain energy metabolism was evaluated via glutamate dehydrogenase activity and ATP levels with ELISA,and enzyme expression was analyzed by immunofluorescence and western blot.Results:Lrg1 knockout decreased neutrophil accumulation and NET formation in mice.3D immunofluorescence reconstruction confirmed neutrophil co-localization with endothelial cells/microglia.scRNA-seq revealed that the oxidative phosphorylation score was significantly higher in the MCAO/R+WT group compared to both the Sham-operated+WT and Lrg1^(-/-)groups.Notably,the oxidative phosphorylation score was further elevated in the MCAO/R+Lrg1^(-/-)group.Immunostaining showed that Lrg1 knockout elevated CD68+lysosome expression post-MCAO/R,with TMEM119 colocalizing with these lysosomes.MCAO/R raised CD68 expression in ischemic brains,an effect further intensified by Lrg1 knockout.KEGG analysis linked differential genes to oxidative phosphorylation pathways.Validation in MCAO/R vs.sham groups revealed increased ROS production and reduced expression of complex enzymes I-V(NDUFB8,SDHB,UQCRC1,MTCO2,ATP5A1).Lrg1 intervention increased enzyme expression.Immunofluorescence and western blot in brain tissue showed similar patterns in microglia and enzymes I-V.Conclusions:Lrg1 knockout significantly enhances microglial phagocytic activity towards neutrophils subsequent to cerebral ischemia-reperfusion injury,through its regulatory effect on the oxidative phosphorylation pathway.This finding accentuates Lrg1 as a highly potential therapeutic target for intervening in and modulating post-ischemic inflammatory responses.展开更多
This study evaluates the findings of Gu et al,who investigated the role of neutrophil gelatinase-associated lipocalin(NGAL)as a biomarker for predicting neuropsychiatric complications in acute ischemic stroke(AIS)pati...This study evaluates the findings of Gu et al,who investigated the role of neutrophil gelatinase-associated lipocalin(NGAL)as a biomarker for predicting neuropsychiatric complications in acute ischemic stroke(AIS)patients.The results revealed that elevated serum NGAL levels at admission are associated with a higher risk of cognitive impairment,anxiety,and depressive symptoms at discharge.The study analyzed 150 AIS patients(mean age 65.4 years,58%male)using the Mini-Mental State Examination and the Hospital Anxiety and Depression Scale to assess neuropsychiatric outcomes.Multivariate analysis demonstrated that higher NGAL levels were independent predictors of cognitive impairment[odds ratio(OR)=1.42],anxiety(OR=1.28),and depression(OR=1.39).Notably,NGAL exhibited strong predictive power for cognitive impairment,with an area under the curve of 0.78.Despite these promising findings,NGAL’s clinical utility is limited by its non-specificity across various conditions.Nevertheless,NGAL levels could help identify AIS patients at risk for neuropsychiatric complications,enabling timely intervention and comprehensive neuropsychiatric evaluation.The study emphasizes the need for further research to validate NGAL’s predictive accuracy and specificity in diverse AIS populations and advocates for its integration with other diagnostic modalities to enhance clinical decision-making.展开更多
基金an Insitutte of National Importance under Ministry of Health and Family Welfare,Government of India,for the Intramural funding for the research study.Project No.95/JIP/Res/Intra-MSc/Phase 2/Grant 3/2016-2017 dated 07.01.2017.
文摘Objective:Urinary tract infection(UTI)is a common cause of morbidity and hospitalisation in the population worldwide.Upper UTI is indolent and causes subclinical acute kidney injury(AKI)resulting in preventable cause of scarring of renal parenchyma.We explored urinary and serum levels of kidney injury molecule-1(KIM-1),haematological parameters and quantitative urine microscopy parameters to predict kidney injury.Methods:Neutrophilelymphocyte ratio(NLR)is obtained by dividing absolute neutrophil count with absolute lymphocyte count.Quantitative urine sediment microscopy was performed and correlated with clinical,biochemical and haematological findings to predict AKI in patients with UTI.Quantitative ELISA was performed for serum and urine levels of KIM-1.Seventy two adult patients with UTI were enrolled,45 of whom had AKI while 27 were in the non-AKI group.Results:NLR(p=0.005)and renal tubular epithelial cell-granular cast score in quantitative urine microscopy(p=0.008)are strong predictors of AKI in patients with UTI while rest of quantitative urine microscopy parameters and serum and urinary levels of KIM-1 molecule were not found to be useful in prediction of AKI.Conclusion:NLR in haemogram is a novel and useful biomarker for predicting AKI in patients with UTI.
基金supported by the National Science Foundation of China,Nos.82325031(to FX),82030059(to YC),82102290(to YG),U23A20485(to YC)Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0505504(to FX),2023ZD0505500(to YC)the Key R&D Program of Shandong Province,No.2022ZLGX03(to YC).
文摘Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.
基金supported by National High Level Hospital Clinical Research Funding,grant nos.BJ-2025-122,BJ2023-126CAMS Innovation Fund for Medical Sciences(CIFMS),grant no.2021-I2M-1050National Natural Science Foundation of China,grant no.82170956。
文摘Chronic obstructive pulmonary disease(COPD),a disease responsible for early mortality worldwide,is well accepted to be associated with periodontitis epidemiologically.Although both of the diseases are the multi-microbial inflammatory disease,the precise underlying mechanisms by which periodontitis influences the progression of COPD remains largely unknown.Here,we established COPD accompanied with periodontitis mouse models and observed the pronounced progress in pulmonary symptoms and histopathology,cha racterized by poorer respiratory function,thicke ned bronchial walls,and increased neutrophils infiltration in lung tissue.Mechanistically,periodontitis pathogen Porphyromonas gingivalis(P.gingivalis)relocated in the lung through the respiratory tract and LPS from P.gingivalis promoted the secretion of chemokines CXCL2 and G-CSF of alveolar epithelial cells through NF-κB and p38 MAPK pathways to recruit neutrophils.Furthermore,exposure to P.gingivalis of infiltrated neutrophils released matrix metallopeptidase-8(MMP-8)and neutrophil elastase(NE),which aggravated airway inflammation and tissue damage.These findings indicated that periodontitis could exacerbate COPD via its pathogen P.gingivalis,which translocated in the lung and stimulated neutrophil chemotaxis and activation in the lung.
文摘Objectives Neutrophil extracellular traps(NETs)have emerged as critical effectors in immune defense but also as potential drivers of tissue damage in chronic inflammatory diseases.Their role in periodontitis,a highly prevalent condition characterized by dysregulated host–microbe interactions,remains incompletely defined.This systematic review aimed to synthesize,for the first time,ex vivo human evidence on the presence,activity,and clinical significance of NETs in periodontitis.Methods A comprehensive search of Medline,Web of Science,and Scopus was conducted up to August 2025.Eligible studies included ex vivo human investigations assessing NETs or NET markers in gingival tissues,gingival crevicular fluid,saliva,blood,or biofilms from patients with periodontitis.Study selection,data extraction,and risk-of-bias assessment were conducted in duplicate,and the protocol was registered in PROSPERO(CRD420251109174).Results Seventeen studies met the inclusion criteria.NET markers such as citrullinated histone H3(CitH3),myeloperoxidase(MPO),and neutrophil elastase were consistently elevated in periodontitis samples compared with controls.Several studies reported a reduction in NET levels or improved NET degradation following periodontal therapy.NETs were also implicated in biofilm stability and in systemic associations with rheumatoid arthritis and chronic kidney disease.However,heterogeneity in methodologies,small sample sizes,and inconsistent marker use limited comparability across studies.Conclusions Ex vivo evidence indicates that aberrant NET formation and impaired clearance contribute to periodontal inflammation and tissue destruction.Nonetheless,methodological variability and risk of bias constrain definitive conclusions.Standardization of detection methods,consensus on marker panels,and exploration of neutrophil subsets and systemic confounders are essential to establish NETs as reliable biomarkers and therapeutic targets in periodontitis.
基金supported by the National Natural Science Foundation of China, Nos.82201474 (to GL), 82071330 (to ZT), and 92148206 (to ZT)Key Research and Discovery Program of Hubei Province, No.2021BCA109 (to ZT)。
文摘Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization.’ There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations(microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.
文摘BACKGROUND The objective of the current study was to elucidate the clinical mechanism through which phospholipase D2(PLD2)exerted a regulatory effect on neutrophil migra-tion,thereby alleviating the progression of acute pancreatitis.AIM To elucidate the clinical mechanism through which PLD2 exerted a regulatory effect on neutrophil migration,thereby alleviating the progression of acute pan-creatitis.METHODS The study involved 90 patients diagnosed with acute pancreatitis,admitted to our hospital between March 2020 and November 2022.A retrospective analysis was conducted,categorizing patients based on Ranson score severity into mild(n=25),moderate(n=30),and severe(n=35)groups.Relevant data was collected for each group.Western blot analysis assessed PLD2 protein expression in patient serum.Real-time reverse transcription polymerase chain reaction was used to evaluate the mRNA expression of chemokine receptors associated with neutrophil migration.Serum levels of inflammatory factors in patients were detected using enzyme-linked immunosorbent assay.Transwell migration tests were conducted to compare migration of neutrophils across groups and analyze the influence of PLD2 on neutrophil migration.RESULTS Overall data analysis did not find significant differences between patient groups(P>0.05).The expression of PLD2 protein in the severe group was lower than that in the moderate and mild groups(P<0.05).The expression level of PLD2 in the moderate group was also lower than that in the mild group(P<0.05).The severity of acute pancreatitis is negatively correlated with PLD2 expression(r=-0.75,P=0.002).The mRNA levels of C-X-C chemokine receptor type 1,C-X-C chemokine receptor type 2,C-C chemokine receptor type 2,and C-C chemokine receptor type 5 in the severe group are significantly higher than those in the moderate and mild groups(P<0.05),and the expression levels in the moderate group are also higher than those in the mild group(P<0.05).The levels of C-reactive protein,tumor necrosis factor-α,interleukin-1β,and interleukin-6 in the severe group were higher than those in the moderate and mild groups(P<0.05),and the levels in the moderate group were also higher than those in the mild group(P<0.05).The number of migrating neutrophils in the severe group was higher than that in the moderate and mild groups(P<0.05),and the moderate group was also higher than the mild group(P<0.05).In addition,the number of migrating neutrophils in the mild group combined with PLD2 inhibitor was higher than that in the mild group(P<0.05),and the number of migrating neutrophils in the moderate group combined with PLD2 inhibitor was higher than that in the moderate group(P<0.05).The number of migrating neutrophils in the severe group+PLD2 inhibitor group was significantly higher than that in the severe group(P<0.05),indicating that PLD2 inhibitors significantly stimulated neutrophil migration.CONCLUSION PLD2 exerted a crucial regulatory role in the pathological progression of acute pancreatitis.Its protein expression varied among patients based on the severity of the disease,and a negative correlation existed between PLD2 expression and disease severity.Additionally,PLD2 appeared to impede acute pancreatitis progression by limiting neutrophil migration.
基金the support of the National Natural Science Foundation of China (Grant No.82272503)Natural Science Foundation of Zhejiang Province (Grant No. LQN25H060006)
文摘Exosomes have shown good potential in ischemic injury disease treatments.However,evidence about their effect and molecular mechanisms in osteonecrosis of femoral head(ONFH)treatment is still limited.Here,we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes(M2-Exos).We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition.Additionally,we identified that M2-Exos’therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adenoassociated virus respectively.Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells.These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.
基金supported by the National Key Research and Development Program of China(NKPs)(2022YFC2604101).
文摘Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019(COVID19).In older individuals,a dysregulated immune response to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection contributes to disease severity;however,the underlying mechanism remains elusive.In this study,we established an aging mouse model of COVID-19,successfully replicating the development of a relatively severe disease in older adults.Further single-cell transcriptome analysis revealed a distinct immune cell landscape in the infected lungs,accompanied by an over-activated inflammatory response,especially in aging mice.Compared to young mice,aging mice showed extensive neutrophil activation,NETosis,and a dramatic decrease in the number of alveolar macrophages(AMs).Moreover,as important executors of efferocytosis,AMs exhibited a low efferocytotic gene signature and downregulation of multiple efferocytosis receptors in aged mice.Further analysis indicated that the efferocytosis of neutrophils,whether undergoing apoptosis or NETosis,was compromised after SARS-CoV-2 infection.Since efferocytosis is a key process in inflammatory resolution,impaired efferocytosis may contribute to hyperinflammation in aging lungs.Our study reveals the characteristics and role of efferocytosis in aging mice after SARS-CoV-2 infection and provides valuable insights for the potential treatment of COVID-19.
基金supported by the National Key R&D Program of China(2023YFA1800100and 2024YFF1206600)the National Natural Science Foundation of China(32100664)the Basic and Applied Basic Research Foundation of Guangdong Province(2024B1515040019 and 2022A1515012042).
文摘Inflammatory bowel disease(IBD)comprises a heterogeneous group of chronic inflammatory conditions of the intestine.Current therapeutic strategies primarily focus on maintaining remission and mitigating the secondary effects rather than reversing its pathogenic mechanisms(Jeong et al.,2019).The pathogenesis of IBD involves intestinal barrier dysfunction,tissue damage,and dysregulated innate and adaptive immune responses(de Souza et al.,2017).Elevated neutrophil activity has been reported in IBD(Danne et al.,2024),yet the precise roles and mechanisms of neutrophils in disease progression remain to be elucidated.
基金supported by National Natural Science Foundation of China grants(Nos.82173326 and 82473058)Key Research and Development Project of Sichuan Province(Nos.2024YFFK0374 and 2024YFFK0198)Interdisciplinary Innovation Project of West China College of Stomatology,Sichuan University(RD-03-202004).
文摘Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell transcriptomics(scRNA-seq)and spatial transcriptomics(ST)to highlight the pivotal role of tumor-associated neutrophils(TANs)among tumor-infiltrating immune cells and their therapeutic response to MTC.MNDA+TANs with anti-tumor activity(N1-phenotype)are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion,and these TANs are characterized by enhanced cytotoxicity,ameliorated hypoxia,and upregulated IL1B,activating T&NK cells and fibroblasts via IL1B-IL1R.In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC,fibroblasts accumulated in the tumor front(TF)can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs(pro-tumor phenotype)via CXCL12-CXCR4,which results in the aggregation of N1-TANs and extracellular matrix(ECM)deposition.In addition,we construct an N1-TANs marker,MX2,which positively correlates with better prognosis in LSCC patients,and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin(H&E)-stained images so as to conveniently guide decision making in clinical practice.Collectively,our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.
文摘Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(anti⁃MDA5+)dermatomyositis(DM)develop into the rapidly progressive interstitial lung disease(RPILD).Methods:We retrospectively analyzed the clinical and laboratory data of 124 anti⁃MDA5+DM patients from the First Affiliated Hospital of Nanjing Medical University between March 2019 and September 2023.We identified independent risk factors associated with the development and mortality of RPILD with the Cox regression analysis,and determined the optimal cut⁃off values for predicting adverse outcomes with the receiver operating characteristic(ROC)curve analysis.Results:Among the 124 patients,36 patients(29.03%)developed RPILD,and 39 patients(31.45%)died during the follow⁃up period.The results of multivariate Cox regression analysis showed that the elevated NLR was an independent risk factor for RPILD development,while the elevated SII expression was independently associated with the increased mortality of RPILD.Based on the ROC curve analysis,NLR>6.12 was a predictor for RPILD,and SII>875.79 was associated with increased mortality risk of RPILD.Conclusion:Both NLR and SII are accessible,cost⁃effective,and reliable prognostic indicators for the prognosis of patients with anti⁃MDA5^(+)DM,providing a valuable guidance for clinical management and risk stratification of the disease.
文摘In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species.Besides,neutrophils will accumulate at the inflammatory site and release NETs,which are composed of histones,DNA and granular proteins.Traumatic heterotopic ossification(THO)was generally believed to develop through four stages:Inflammation,chondrogenesis,osteogenesis,and bone maturation.Thus,it can be seen that THO was related to inflammation and bone formation.Apart from immune and infectious diseases,recent studies have also shown that NETs play a significant role in the pathogenesis of THO.This article focuses on elaborating the role of NETs in the onset of THO,discussing the existing problems in the current research and outlining future directions.
基金Supported by Slovak Research and Development Agency,No.APVV-21-0370Ministry of Education,Science,Research and Sport of the Slovak Republic,No.VEGA 1/0706/25 and No.VEGA 1/0341/23.
文摘BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD)is a prevalent chronic liver disorder driven by obesity and metabolic dysfunction.MASLD progresses to metabolic dysfunction-associated steatohepatitis,which is characterized by inflammation,hepatocyte injury,and fibrosis,increasing the risk of cirrhosis and liver failure.Recent studies suggest that neutrophil extracellular traps(NETs)and extracellular DNA(ecDNA)contribute to liver inflammation and fibrogenesis.However,their role in MASLD pathogenesis remains incompletely understood.AIM To investigate the dynamics of circulating NETs and ecDNA as potential biomarkers of liver injury in MASLD.METHODS Using three complementary mouse models,thioacetamide(TAA)-induced fibrosis,choline-deficient L-amino acid-defined(CDAA)diet-induced metabolic dysfunction-associated steatohepatitis,and cafeteria(CAF)diet-induced MASLD,we assessed the association between NET-related markers and liver damage.Blood samples were collected biweekly to analyze ecDNA and NET markers,including myeloperoxidase(MPO)and MPO-DNA complexes,using ELISA and real-time PCR.Liver histopathology was assessed for inflammation,fibrosis,and neutrophil infiltration.RESULTS The TAA and CDAA models exhibited significant liver injury,characterized by increased plasma alanine aminotransferase and aspartate aminotransferase levels,hepatocellular damage,and fibrosis.Elevated circulating NET markers(MPO and ecDNA)were observed in these models,with a strong correlation between NET formation and liver pathology.The CAF diet model induced steatosis but failed to elicit significant liver fibrosis or an increase in NET markers,suggesting that NETosis is associated with more severe liver damage.Notably,ecDNA and MPO levels correlated with neutrophil infiltration and fibrosis scores,indicating their potential as biomarkers of MASLD progression.CONCLUSION NETosis and ecDNA levels reflect liver injury severity in MASLD.NET markers and liver fibrosis were strongly associated in TAA and CDAA models,whereas CAF model showed minimal NET involvement.
基金supported by the National Natural Science Foundation of China(Grant nos.82473157,82460510,82203565,82103388,31960145 and 82560591)the Natural Science Foundation of Beijing(Grant no.L248059)+1 种基金Yunnan Province applied research funds(Grant nos.202201AY070001-011,202201AY070001-043,and 202301AS070018)the Science and Technology Innovation Team of tumor metabolism research at Kunming Medical University(Grant no.CXTD202102).
文摘Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.
基金funded by grants from the National Natural Science Foundation of China(Grant Nos.82373263 and 82403835)the National Key Research and Development Program of China(Grant No.2023YFC2506400)+2 种基金China Postdoctoral Science Foundation(Grant No.2024M751405)Jiangsu Provincial Natural Science Foundation Youth Project(Grant No.BK20240247)General Project of Nanjing Health Science and Technology Development Program(Grant No.YKK24084).
文摘Tumor-associated neutrophils(TANs)exhibit highly func-tional heterogeneity across cancers.Although TANs pro-mote inflammatory responses and contribute to tumor clearance,they frequently undergo context-dependent reprogramming within the tumor microenvironment(TME)into highly immunosuppressive phenotypes that facilitate cancer dissemination and immunotherapy resist-ance1,2.We contend that an underappreciated,upstream determinant of this divergence is the maturation stage of TANs3,4.The developmental stage of TANs determines the migration patterns and constrains the functional capacity,and the developmental stage also constrains the extent of TME-driven re-education,together shaping pro-or anti-tu-mor outcomes3-5.In this Perspective,we place maturation at the core of TAN biology and discuss current definitions for TAN developmental stages and the measurable mark-ers that researchers and clinicians can use(Figure 1).In addition,spatial and temporal transitions in TAN matu-ration stages and the factors that govern these transitions are elucidated.We explain how maturation status shapes TAN function and articulate the key differences between mouse and human TAN maturation systems to highlight the value of human immune system(HIS)mouse models.Based on this framework,functional biomarkers and signa-tures of TAN maturation are introduced and we show how to embed them into patient stratification and longitudinal monitoring.Finally,we outline immunotherapy strategies targeting TAN maturation,selecting interventions guided by maturation markers to reinforce treatment benefits for cancer patients.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82273449 and 82203663)the Zhejiang Provincial Natural Science Foundation of China(Grant No.LQ23H160013)the Medical and Health Science and Technology Project of Zhejiang Province(Grant Nos.2024KY1039 and 2024KY1250).
文摘Neutrophils are the protagonists of the host immune response,possessing potent antimicrobial and inflammatory capacities.The neutrophil reservoir as well as the development,mobilization,chemotaxis,pro-inflammatory activity,and clearance of neutrophils are strictly regulated to prevent inflammation-induced tissue damage.Inflammation pervades almost every type of cancer.However,there is growing awareness that although the tumor microenvironment has the capacity to recruit neutrophils,the functions are diverse and include roles other than that of sentinels in cancer.This review highlights the heterogeneity of neutrophils in tumors,discusses the dual role of neutrophils as angels and demons in tumorigenesis,invasion,and metastasis,and examines the potential of neutrophils as targets in clinical therapy.
基金supported by NIH grants to MI Bukrinsky(R01NS124477 and P30AI117970)by the“Creation of Experimental Laboratories in the Natural Sciences Program”and Basic Research Programat Higher School of Economics University.
文摘Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins released by neutrophils,contribute significantly to both inflammation and thrombosis.This manuscript offers a comprehensive review of the recent literature on the involvement of NET in atherosclerosis,highlighting their interactions with various pathophysiological processes and their potential as biomarkers for CVD.Notably,the impact of radiation on NET formation is explored,emphasising how oxidative stress and inflammatory responses drive NET release,contributing to plaque instability.The role of histones,particularly citrullinated histones,in endothelial dysfunction and plaque progression is discussed,highlighting their significance in the pathophysiology of atherosclerosis.Furthermore,the complex relationship between lipoproteins and NET formation is examined,with a focus on how elevated low-density lipoprotein(LDL)and decreased high-density lipoprotein(HDL)levels facilitate NET release,thus promoting vascular inflammation and plaque instability.The influence of cholesterol on NET formation is also explored,underscoring its contribution to plaque development and stability.The role of Peptidylarginine deiminase 4(PAD4)in the regulation of NETosis is reviewed,with attention given to how PAD4-driven citrullination of histones affects atherosclerosis progression.Moreover,the manuscript examines the potential of NET components—such as double-stranded DNA,myeloperoxidase–DNA complexes,and citrullinated histone H3—as biomarkers for assessing disease severity and predicting adverse cardiovascular events,including ST-elevation myocardial infarction(STEMI)and stroke.Elevated levels of these biomarkers correlate with worse clinical outcomes,suggesting their utility in guiding therapeutic interventions.In contrast to the existing body of work,this review highlights the novelty of integrating recent findings on NET interactions with lipid metabolism,histone modifications,and PAD4 activity in the context of atherosclerosis.Overall,NET plays an integral role in the inflammatory and thrombotic processes underpinning atherosclerosis,and their components hold promise as both diagnostic markers and therapeutic targets in cardiovascular disease management.
基金Supported by 2024 Suining Health Science and Technology Plan Project,No.24ZDJB03.
文摘Neutrophil extracellular traps(NETs)have been the subject of research in the field of innate immunity since they were first described two decades ago.NETs are fibrous network structures released by neutrophils under specific stimuli,including DNA,histones,and a variety of granular proteins.NETs have been widely studied in the fields of infectious and immune diseases,and new break-throughs have been made in the understanding of disease pathogenesis and treatment.In recent years,studies have found that NETs play an important role in the occurrence and development of osteoarticular diseases.This article reviews the progress in the research of NETs in common osteoarticular diseases such as rheumatoid arthritis,ankylosing spondylitis,gouty arthritis,osteonecrosis of the femoral head,osteoarthritis,and joint fibrosis,including the formation mecha-nism of NETs and its role in inflammation,joint destruction,pain and other pa-thological processes.The problems existing in current research are discussed,along with future research directions,to provide a reference for the in-depth study of osteoarticular diseases and the development of new treatment strategies.
基金supported by the Foundation Project:National Natural Science Foundation of China(Nos.:82460249,82100417,81760094)The Foundation of Jiangxi Provincial Department of Science and Technology Outstanding Youth Fund Project(20242BAB23080).
文摘ABSTRACT:Background:After ischemic stroke,neutrophils hyperactivate,increasing in number and worsening inflammation,causing neural damage.Prior scRNA-seq showed Lrg1 modulates cells subsentence to cerebral ischemiareperfusion injury,but its mechanism in regulating neutrophil accumulation/differentiation post-injury is unclear.Methods:Lrg1 knockout impact on neutrophil accumulation was assessed via immunofluorescence and western blot.Three-dimensional reconstruction of immunofluorescent staining analyzed cell-cell interactions among neutrophils and microglia.scRNA-seq of WT and Lrg1^(-/-)mice from GSE245386 and GSE279462 was conducted.Each group conducted oxidative phosphorylation scoring via Gene Set Enrichment Analysis(GSEA),while Metascape was employed to perform GO and KEGG enrichment analyses for elucidating functional mechanisms.CellChat exhibited cell-cell communication.Furthermore,alterations in microglial phagocytic activity were evaluated by immunostaining for CD68,a well-established marker of phagolysosomal activity in phagocytic cells.Brain energy metabolism was evaluated via glutamate dehydrogenase activity and ATP levels with ELISA,and enzyme expression was analyzed by immunofluorescence and western blot.Results:Lrg1 knockout decreased neutrophil accumulation and NET formation in mice.3D immunofluorescence reconstruction confirmed neutrophil co-localization with endothelial cells/microglia.scRNA-seq revealed that the oxidative phosphorylation score was significantly higher in the MCAO/R+WT group compared to both the Sham-operated+WT and Lrg1^(-/-)groups.Notably,the oxidative phosphorylation score was further elevated in the MCAO/R+Lrg1^(-/-)group.Immunostaining showed that Lrg1 knockout elevated CD68+lysosome expression post-MCAO/R,with TMEM119 colocalizing with these lysosomes.MCAO/R raised CD68 expression in ischemic brains,an effect further intensified by Lrg1 knockout.KEGG analysis linked differential genes to oxidative phosphorylation pathways.Validation in MCAO/R vs.sham groups revealed increased ROS production and reduced expression of complex enzymes I-V(NDUFB8,SDHB,UQCRC1,MTCO2,ATP5A1).Lrg1 intervention increased enzyme expression.Immunofluorescence and western blot in brain tissue showed similar patterns in microglia and enzymes I-V.Conclusions:Lrg1 knockout significantly enhances microglial phagocytic activity towards neutrophils subsequent to cerebral ischemia-reperfusion injury,through its regulatory effect on the oxidative phosphorylation pathway.This finding accentuates Lrg1 as a highly potential therapeutic target for intervening in and modulating post-ischemic inflammatory responses.
基金Supported by the Basic Science Research Program through the National Research Foundation of Korea Funded by the Ministry of Education,No.RS-2023-00237287Regional Innovation Strategy Through the National Research Foundation of Korea Funded by the Ministry of Education,No.2021RIS-003.
文摘This study evaluates the findings of Gu et al,who investigated the role of neutrophil gelatinase-associated lipocalin(NGAL)as a biomarker for predicting neuropsychiatric complications in acute ischemic stroke(AIS)patients.The results revealed that elevated serum NGAL levels at admission are associated with a higher risk of cognitive impairment,anxiety,and depressive symptoms at discharge.The study analyzed 150 AIS patients(mean age 65.4 years,58%male)using the Mini-Mental State Examination and the Hospital Anxiety and Depression Scale to assess neuropsychiatric outcomes.Multivariate analysis demonstrated that higher NGAL levels were independent predictors of cognitive impairment[odds ratio(OR)=1.42],anxiety(OR=1.28),and depression(OR=1.39).Notably,NGAL exhibited strong predictive power for cognitive impairment,with an area under the curve of 0.78.Despite these promising findings,NGAL’s clinical utility is limited by its non-specificity across various conditions.Nevertheless,NGAL levels could help identify AIS patients at risk for neuropsychiatric complications,enabling timely intervention and comprehensive neuropsychiatric evaluation.The study emphasizes the need for further research to validate NGAL’s predictive accuracy and specificity in diverse AIS populations and advocates for its integration with other diagnostic modalities to enhance clinical decision-making.
